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Purpose: Gallbladder cancer is a lethal malignancy of hepato-biliary system with high incidence in North India, especially along gangetic plain. The let-7 microRNAs play a key role in regulating KRAS expression and a polymorphism in 3' untranslated region (rs61764370, T/G) of KRAS leads to its higher expression. This polymorphism is known to be associated with increased risk and prognosis of various cancers but its association with gallbladder cancer has not been evaluated. To address this research question, we evaluated whether rs61764370 variant is associated with gallbladder cancer susceptibility and clinical outcomes., Methods: In present case-control study, we enrolled 541 patients with gallbladder malignancy and 307 controls. Genomic DNA was obtained from peripheral blood and genotyping was performed using Taqman allelic discrimination assay., Results: Heterozygous (TG) individuals are at a significant higher risk for GBC as compared with wild genotype (TT) (p = 0.007, odds ratio = 2.56, 95 % CI 1.27-5.18). At allelic level, allele G has significant higher risk for GBC as compared with T allele (p = 0.008, odds ratio = 2.5, 95 % CI 1.25-5.01). Survival analysis reveals decrease in overall survival for heterozygous genotype (p < 0.0001, hazard ratio = 3.42, 95 % CI 1.21-4.20). Also, significant decrease in overall survival was observed for patient carrying allele G (p < 0.0001, HR = 2.89, 95 % CI 1.21-4.20) as compared with allele C., Conclusions: We conclude that KRAS rs61764370 polymorphism is significantly associated with risk and prognosis of gallbladder malignancy in this endemic belt.

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract with adverse prognosis and poor survival. Wnt signaling plays an important role in embryonic development and regeneration of tissues in all the species. Deregulation of expression and mutations in this pathway may lead to disease state such as cancer. In this study, we assessed the association of common germline variants of Wnt pathway genes (SFRP2, SFRP4, DKK2, DKK3, WISP3, APC, β-catenin, AXIN-2, GLI-1) to evaluate their contribution in predisposition to GBC and treatment outcomes. The study included 564 GBC patients and 250 controls. Out of 564, 200 patients were followed up for treatment response and survival. Tumor response (RECIST 1.1) was recorded in 116 patients undergoing non-adjuvant chemotherapy (NACT). Survival was assessed by Kaplan-Meier curve and Cox-proportional hazard regression. Single locus analysis showed significant association of SFRP4 rs1802073G > T [p value = 0.0001], DKK2 rs17037102C > T [p value = 0.0001], DKK3 rs3206824C > T [p value = 0.012], APC rs4595552 A/T [p value = 0.021], APC rs11954856G > T [p value = 0.047], AXIN-2 rs4791171C > T [p value = 0.001], β-catenin rs4135385A > G [p value = 0.031], and GLI-1 rs222826C > G [p value = 0.001] with increased risk of GBC. Gene-gene interaction using GMDR analysis predicted APC rs11954856 and AXIN2 rs4791171 as significant in conferring GBC susceptibility. Cox-proportional hazard model showed GLI-1 rs2228226 CG/GG and AXIN-2 rs4791171 TT genotype higher hazard ratio. In recursive partitioning, AXIN-2 rs4791171 TT genotype showed higher mortality and hazard. Most of studied genetic variants influence GBC susceptibility. APC rs11954856, GLI-1 rs2228226, and AXIN-2 rs4791171 were found to be associated with poor survival in advanced GBC patients.

Genes important to stem cell progression have been involved in the genetics and clinical outcome of cancers. We investigated germ line variants in cancer stem cell (CSC) genes to predict susceptibility and efficacy of chemoradiotherapy treatment in gallbladder cancer (GBC) patients. In this study, we assessed the effect of SNPs in CSC genes (surface markers CD44, ALCAM, EpCAM, CD133) and (molecular markers NANOG, SOX-2, LIN-28A, ALDH1A1, OCT-4) with GBC susceptibility and prognosis. Total 610 GBC patients and 250 controls were genotyped by using PCR-RFLP, ARMS-PCR, and TaqMan allelic discrimination assays. Chemotoxicity graded 2-4 in 200 patients and tumor response was recorded in 140 patients undergoing neoadjuvant chemotherapy (NACT). Differences in genotype and haplotype frequency distributions were calculated by binary logistic regression. Gene-gene interaction model was analyzed by generalized multifactor dimensionality reduction (GMDR). Overall survival was assessed by Kaplan-Meier survival curve and multivariate Cox-proportional methods. ALCAM Ars1157Crs10511244 (P = 0.0035) haplotype was significantly associated with GBC susceptibility. In GMDR analysis, ALCAM rs1157G>A, EpCAM rs1126497T>C emerged as best significant interaction model with GBC susceptibility and ALDH1A1 rs13959T>G with increased risk of grade 3-4 hematological toxicity. SOX-2 rs11915160A>C, OCT-4 rs3130932T>G, and NANOG rs11055786T>C were found best gene-gene interaction model for predicting response to NACT. In both Cox-proportional and recursive partitioning ALCAM rs1157GA+AA genotype showed higher mortality and hazard ratio. ALCAM gene polymorphisms associated with GBC susceptibility and survival while OCT-4, SOX-2, and NANOG variants showed an interactive role with treatment response.

Introduction: miR-27a, miR-181a, and miR-570 genetic variants have been found to play an important role in many cancers, but their contribution in gallbladder carcinoma (GBC) has not been explored. Therefore, we investigated the role of these micro RNA (miRNA) genetic variants in terms of GBC susceptibility, therapeutic response, toxicities associated with chemo-radiotherapy and survival outcome., Methods: This study included 606 GBC patients and 200 healthy controls. From among the larger study cohort, 219 patients receiving adjuvant or palliative chemo-radiotherapy as per disease status were followed up for toxicity profile. Treatment response was recorded in 159 patients who received palliative chemo-radiotherapy. Genotypes were determined using allelic discrimination assay. Statistical analysis was carried out with SPSS version 16. Generalized multifactor dimensionality reduction (GMDR) analysis was performed for gene-gene interactions. Survival analysis was performed using Kaplan-Meier and Cox regression tests., Results: In univariate logistic regression analysis, no association with any of the studied polymorphisms was found in overall GBC susceptibility. Furthermore, univariate and multivariate analyses revealed no significant association with response to chemo-radiotherapy. In GMDR analysis, miR-27ars895819, miR-570rs4143815, and miR-181ars12537 combination was found as the best gene-gene interaction model for susceptibility and treatment response. Furthermore, miR-27ars895819miR-181ars12537 was associated with neutropenia toxicity in patients undergoing chemo-radiotherapy. However, miRNA variants had no influence over the survival outcomes of GBC patients (locally advanced, metastatic)., Conclusion: In conclusion, the miRNA variants cumulatively influence GBC susceptibility and treatment outcomes.

CD44 is an important marker for cancer stem cells. Germline variants in CD44 gene have been associated with susceptibility to breast and nasopharyngeal carcinomas but no study in gallbladder cancer (GBC) has been done yet. The present study included 405 GBC patients and 200 healthy controls from North India. Tagger SNPs for CD44 were selected from the GIH population data. Genotyping was carried out by PCR-RFLP and Taqman probes. Statistical analysis was done by SPSS. Bonferroni correction was applied in subgroup analysis. Logistic regression analysis showed no individual association of CD44 polymorphisms with GBC risk. However, [CCAT] haplotype was associated with overall reduced risk of GBC [P = 0.04, odds ratios (OR) = 0.47]. Gender stratification revealed that [CCAT] and [TAGT] haplotypes were significantly associated with decreased risk in female GBC patients [P = 0.022, OR = 0.38; P = 0.011, OR = 0.17, respectively]. The CAAT haplotype was marginally associated with low GBC risk in patients with co-existing gallstones [P = 0.026, OR = 0.53]. The cancer risk was not further modified with tobacco usage or age of onset. In silico analysis showed change in transcriptional regulation of selected SNPs. This study reports an important role of CD44 haplotypes with reduced risk of GBC.

Genetic alterations in the deleted in colorectal carcinoma (DCC) gene have been a priori reported to associate with metastasis in variety of human cancers. We investigated the association between potentially functional SNPs in DCC and susceptibility to esophageal (EC) and gastric (GC) cancers in Kashmir Valley. We genotyped two SNPs DCC rs714 (A>G) and DCC rs2229080 (C>G) of DCC in 135 EC patients, 108 GC patients, and 195 controls matched by age and sex in Kashmir Valley by polymerase chain reaction-RFLP method. Risk for developing EC and GC was estimated by binary logistic regression by using SPSS. We also performed a meta-analysis on DCC rs714 (A>G) and evaluated the association between the DCC rs714 (A>G) polymorphisms and cancer risk. A significant difference in DCC rs714 (A>G) genotype distribution between EC and GC cases and corresponding control groups was observed (odds ratio (OR) = 1.92; P = 0.03; P-trend = 0.04; false discovery rate (FDR) Pcorr = 0.03: OR = 2.15; P = 0.02; P-trend = 0.01; FDR Pcorr = 0.03). But no such association was observed in DCC rs2229080 (C>G). Further, DCC rs714 (A>G) AA genotype showed significantly increased risk for both gastric squamous cell carcinoma (OR = 5.63; P = 0.02; FDR Pcorr = 0.01) and gastric adenocarcinoma (OR = 2.15; P = 0.02; FDR Pcorr = 0.01). Smoking and salted tea are independently associated with both EC and GC, but gene-environment interaction did not further modulate the risk. Meta-analysis also suggested both independent and overall association of DCC rs714 (A>G) polymorphism with cancer (P = 0.000). In conclusion, genetic variations in DCC rs714 (A>G) modulate risk of EC and GC in high-risk Kashmir population.